Differential virulence of Trypanosoma brucei rhodesiense isolates does not influence the outcome of treatment with anti-trypanosomal drugs in the mouse model

Abstract

We assessed the virulence and anti-trypanosomal drug sensitivity patterns of Trypanosoma brucei rhodesiense (Tbr) isolates in the Kenya Agricultural and Livestock Research Organization-Biotechnology Research Institute (KALRO-BioRI) cryobank. Specifically, the study focused on Tbr clones originally isolated from the western Kenya/eastern Uganda focus of human African Trypanosomiasis (HAT). Twelve (12) Tbr clones were assessed for virulence using groups(n = 10) of Swiss White Mice monitored for 60 days post infection (dpi). Based on survival time, four classes of virulence were identified: (a) very-acute: 0–15, (b) acute: 16–30, (c) sub-acute: 31–45 and (d) chronic: 46–60 dpi. Other virulence biomarkers identified included: pre-patent period (pp), parasitaemia progression, packed cell volume (PCV) and body weight changes. The test Tbr clones together with KALRO-BioRi reference drug-resistant and drug sensitive isolates were then tested for sensitivity to melarsoprol (mel B), pentamidine, diminazene aceturate and suramin, using mice groups (n = 5) treated with single doses of each drug at 24 hours post infection. Our results showed that the clones were distributed among four classes of virulence as follows: 3/12 (very-acute), 3/12 (acute), 2/12 (sub-acute) and 4/12 (chronic) isolates. Differences in survivorship, parasitaemia progression and PCV were significant (P<0.001) and correlated. The isolate considered to be drug resistant at KALRO-BioRI, KETRI 2538, was confirmed to be resistant to melarsoprol, pentamidine and diminazene aceturate but it was not resistant to suramin. A cure rate of at least 80% was achieved for all test isolates with melarsoprol (1mg/Kg and 20 mg/kg), pentamidine (5 and 20 mg/kg), diminazene aceturate (5 mg/kg) and suramin (5 mg/kg) indicating that the isolates were not resistant to any of the drugs despite the differences in virulence. This study provides evidence of variations in virulence of Tbr clones from a single HAT focus and confirms that this variations is not a significant determinant of isolate sensitivity to anti-trypanosomal drugs.

The pathogenicity of blood stream and central nervous system forms of Trypanosoma brucei rhodesiense trypanosomes in laboratory mice: a comparative study

“…These results confirmed the existence of differential virulence among the isolates. Differential virulence and pathogenicity of trypanosomes has previously also been reported for other samples of Tyrpanosoma brucei rhodesiense isolates in mice, 28 Trypanosoma brucei rhodesiense isolates in vervet monkeys 29 ; Trypanosoma brucei brucei and Trypanosoma congolense strains in mice 25,31-33 and T. evansi isolates in mice. 34 In the present work, we have additionally shown that mice groups infected with CNS derived trypanosomes also exhibited differential virulence, indicating that this attribute is independent of the environment from which the trypanosomes are recovered.…”

“…High trypanosome numbers are frequently, but not always, associated with increased pathogenicity. 28,39 We monitored the development of anaemia which is one of the major trypanosome-induced pathologies and is a possible biomarker of parasite pathogenicity and virulence. The main characteristic of the murine trypanosome-induced anaemia was the rapidity of its onset in all the infected mice as shown by PCV declines by an average of 30% by 14 days post infection.…”

Variation of sensitivity of Trypanosoma evansi isolates from Isiolo and Marsabit counties of Kenya to locally available trypanocidal drugs

“…In addition, the multiple drug resistance observed in this study is at the population level and most likely not at the individual trypanosome level where treatment using a “sanative pair” would have been impossible [ 42 ]. Ndungu et al [ 30 ] demonstrated that several clones derived from an isolate that exhibited resistance to trypanocidal drugs in mice showed variable sensitivity to treatment. Whether the clones from the multiple resistant isolates from this study could have variable sensitivity to diminazene, homidium and isometamidium was not investigated.…”

“…Studies have shown that resistant trypanosome populations vary greatly in the sensitivity of individual trypanosomes in that population [ 27 – 29 ]. In addition, Ndung’u et al [ 30 ] demonstrated the existence of variations in virulence and sensitivity of T . b .…”

“…Studies have shown that resistant trypanosome populations vary greatly in the sensitivity of individual trypanosomes in that population [27][28][29]. In addition, Ndung'u et al [30] demonstrated the existence of variations in virulence and sensitivity of T. b. rhodesiense cloned stabilates from one isolate. This suggests that drug resistant populations can be effectively treated by increasing the dosage or through multiple treatment [17,31], or through combination of different synergistic trypanocides [32].…”